title: Mixed blockade of K+ and Na+ currents in rat ventricular myocytes by the tedisamil analogue, KC8851.
abstract: The whole-cell voltage clamp method has been used to study the actions of KC8851, a structural analogue of tedisamil (KC8857), on the transient outward K+ current (Ito) and the Na+ current (INa) in rat ventricular myocytes. KC8851 diminished the inactivation time course of Ito with an EC50 value of 2.2 microM. Kinetic analysis of the time-dependent effects of KC8851 on the decay of Ito was consistent with open channel blockade with respective blocking and unblocking rate constants of 9.3 X 10(6) M(-1) s(-1) and 19.3 s(-1). KC8851 was also found to be a potent inhibitor of peak Na+ current with an EC50 value of 5.1 microM. The inhibition of INa was primarily use-dependent with some contribution from tonic block. The results show KC8851 exhibits potent and selective mixed blockade of Ito and INa a result different from that previously documented for the analogue, tedisamil, which was found to be a potent blocker of Ito, but not INa, in rat ventricular cells.
authors.affiliation: Department of Pharmacology and Therapeutics, Faculty of Medicine, The University of British Columbia, Vancouver, Canada. mclarnon@unixg.ubc.ca
authors.forename: J G
authors.initials: JG
authors.lastname: McLarnon
authors.forename: R
authors.initials: R
authors.lastname: Xu
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000737:chemistry / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry / Q000494:pharmacology*; D003521:Cyclopropanes / Q000737:chemistry / Q000494:pharmacology*; D004594:Electrophysiology; D005260:Female; D006352:Heart Ventricles / Q000187:drug effects; D017136:Ion Transport / Q000187:drug effects; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D015222:Sodium Channels / Q000187:drug effects* / Q000502:physiology; D016276:Ventricular Function
chemical_list: D000889:Anti-Arrhythmia Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003521:Cyclopropanes; D015221:Potassium Channels; D015222:Sodium Channels; C106999:KC 8851